This disclosure relates to control of biofouling in implantable biosensors. In particular, this disclosure relates to a biofouling inhibiting coating for a biosensor that may be installed inside the body of a living being.
Miniaturized, implantable biosensors form an important class of biosensors because of their ability to continuously monitor metabolite(s) level(s) without the need for patient intervention and regardless of the patient's physiological state (rest, sleep, exercise, and the like). Such continuous monitoring is important for the treatment of certain diseases such as Diabetes Mellitus and to avoid associated complications such as obesity, renal failure and blindness. However, the development of these implantable biosensors have been impeded since they are not capable of reliable in vivo monitoring for longer than a few hours without the need for repeated calibration.
This instability is considered to be a result of a constantly changing in vivo environment that these sensors experience following their implantation. Tissue inflammation and foreign body response sets in within short periods of time after sensor implantation. While the former is caused by the tissue injury that results from implantation of the device as well as the continual presence of the device in the body, the latter is a result of the body's natural response to ultimately encapsulate the implanted device with fibrotic tissue and prevent it from interacting with the surrounding tissue. FIG. 1 is a schematic representation of the process of biofouling (A) following sensor implantation. Such biofouling eventually signals a cascade of events to lead to the formation of fibrotic band (B), which completely blocks analyte diffusion to the implantable biosensor.
Along with these processes, the implanted sensor is continuously inundated with low molecular weight proteins (in the order of few KDa) along with cells (in the order of 10 to 100 microns) within a short period of time following implantation. The small molecular weight proteins penetrate and clog the sensor membrane(s) while the cells deposit on the outer sensor surface (FIG. 1(B)). These two actions cause a severe mass transfer barrier for analyte diffusion to the sensing element, thereby degrading the in vivo sensor performance and long-term stability. Such degradation in sensor performance typically necessitates periodic sensor calibration using an external analyte monitoring device via finger pricking.
In order to alleviate the issue of in vivo sensor degradation, various biocompatible coatings (such as Nafion, hyaluronic acid, humic acids, phosphorylcholine, 2-methacryloyloxyethyl phosphorylcholine, polyurethanes with phospholipid polar groups, poly vinyl alcohol hydrogels, betaines, and the like) have been employed. These membranes are intended to: (i) maintain a desired, yet constant flux of passage of analyte molecules over long periods of time, (ii) reduce protein adsorption, and (iii) promote integration of the sensor with the surrounding tissues. However, the success of these strategies is ultimately impeded by the action of multi-valent ions that in combination with flexible and charged, low molecular weight protein fragments and large charged cell deposits forms stable complexes that are difficult to dissociate within the restrained environments of either inner membranes or outer membrane/tissue interface.
In another approach, “textured” rather than “smooth” implant surfaces have been employed in order to mitigate biofouling. This arises from the fact that nanostructured membranes have a different contact angle and therefore a different degree of hydrophobicity/hydrophilicity from a regular smooth membrane which repels the adsorption of large charged cells onto the surface of the implant. However, these methodologies are costly and difficult to be implemented in conjunction with the miniaturization requirements of an implantable device. Moreover, the possible toxicity of the nanostructured materials used to create textured surfaces is a concern and can cause an enormous increase in regulatory burden.
Researchers have also pursued smart nanoporous materials that change their permeability in response to environmental stimuli such as pH, temperature ionic/solute concentration, as well as magnetic and electric fields. Most of these smart nanoporous materials work on the basis of reversible expansion and collapse of responsive polymers incorporated within their pores. An extension to this approach has been the incorporation of magnetostrictive materials to induce local oscillating/vibrational motions upon the application of external stimuli. Both these methodologies are intended to cause protein desorption. However, the incorporation of such elements are proven costly and difficult, especially considering the desire for miniaturization of all implantable systems. Moreover, the possible toxicity of these nanomaterials is undetermined and could increase regulatory burden.
In yet another attempt at mitigating bioadhesion of tissue to the biosensor, proteases have been incorporated into a variety of different matrices to reduce the binding of proteins to surfaces by degrading adsorbed biomolecules. However, considering the large matrix of proteins available in the human physiology and the confined space of the outer membrane, their ability to yield a 100% efficacy is compromised. Moreover, the inherent stability of these proteases is also of a concern.
More recently nanocomposite coatings where nanomaterials are embedded within in a polymer matrix are also being used to reduce biofouling. Nanocomposite coatings based on carbon nanotubes and silica nanoparticles have been used to reduce biofouling. However, the success of these approaches has been limited so far. Similarly, the toxicity of these nanomaterials is questionable and can increase the regulatory burden.
In yet another approach, microsphere-based drug-delivery coatings have been utilized to reduce inflammation via localized delivery of anti-inflammatory drugs. These coatings, while capable of minimizing mid and long-term tissue inflammation and fibrotic encapsulation, they are unable to mitigate the short-term effects from protein and cell adsorption. Consequently, the issue of protein biofouling and cell adhesion remains to be a problem which leads to constant changes in analyte permeability over the entire duration of in vivo sensor operation.